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Safety and application of induced sputum analysis in childhood asthma
The Editors’ Choice Donald Y. M. Leung, MD, PhD Harold S. Nelson, MD Stanley J. Szefler, MD William W. Busse, MD
The puzzle of IL-8 and the genetics of inflammation There is an important clinical feature that bronchial asthma, juvenile idiopathic arthritis (JIA), and respiratory syncytial virus (RSV)–triggered bronchiolitis have in common: the inflammatory reaction. Given that inflammatory processes are strongly influenced by genetic factors, some common genetic basis of all 3 diseases might be suspected. The article by Heinzmann et al in this issue of the Journal (p 671) focuses on the IL-8 pathway. IL-8 represents a strong inducer of inflammation. Several polymorphisms in its coding gene have been published, one
Finding NEMO Human mutations in the gene IKBKG on the X-chromosome that encodes the nuclear factor-jB essential modulator (NEMO) protein have been associated with the syndrome of ectodermal dysplasia and immunodeficiency in males. This syndrome is characterized by absent eccrine sweat glands, sparse hair, conical incisors, and combined immunodeficiency. Patients have severe bacterial infections and susceptibility to atypical mycobacteria. The NEMO protein serves as a critical link between important receptor systems and the transcription factor NFKB. When NFKB is appropriately activated by NEMO, it can travel into the nucleus to induce gene transcription. As
Safety and application of induced sputum analysis in childhood asthma The Childhood Asthma Management Program (CAMP) evaluated the long-term effects of budesonide and nedocromil compared with placebo in children with mild to moderate asthma. In this ancillary study by Covar et al, from the Denver CAMP site (p 575), biomarkers of airway inflammation were evaluated. At discontinuation of treatment, budesonide-treated patients had lower median sputum percent eosinophils, exhaled nitric oxide levels, and serum IgE and higher prebronchodilator FEV1% predicted than patients treated with placebo; no significant difference was noted between nedocromil- and placebo-treated patients. Higher sputum percent
J ALLERGY CLIN IMMUNOL
THE JOURNAL OF
Allergy Clinical Immunology AND
VOLUME 114
NUMBER 3
of them in close association with RSV-triggered bronchiolitis. The very same polymorphisms are now presented for the first time in association with bronchial asthma. This finding by itself might not be surprising; however, it is surprising to look at the kind of association. Bronchial asthma shows inverted association effects compared with bronchiolitis and, as well, in direct comparison with JIA. In other words, the genetic risk factor for bronchial asthma in the IL-8 gene represents a protective factor for bronchiolitis and JIA and vice versa. These findings might assist in our understanding of the pathophysiologic pathways in different inflammatory reactions. However, they underline as well the complexity of the genetic basis of inflammatory diseases.
a result of deficient NEMO activity, many functions of immune cells are impaired, including class switch recombination, specific antibody production, natural killer cell cytotoxicity, and Toll-like receptor responses. In this issue of the Journal, Orange et al (p 650), have identified a patient with an IKBKG mutation having the characteristic associated immunodeficiency but without ectodermal dysplasia. This patient is the first male reported to have immunodeficiency and normal ectoderm with an IKBKG mutation. The existence of this patient means that the absence of ectodermal dysplasia in an immunodeficient boy does not exclude IKBKG mutation as the etiology. It also suggests that important genotype/phenotype correlations are a feature of mutant NEMO molecules.
eosinophils was associated with atopy, higher bronchodilator reversibility, a lower FEV1/FVC ratio, higher exhaled nitric oxide levels, circulating eosinophil levels, sputum and serum eosinophil cationic protein levels, more prednisone courses during the treatment period, and greater asthma severity. Despite the relative safety and tolerability of sputum induction in children, 23% were not able to provide an adequate sputum sample for analysis. In 8%, sputum induction resulted in bronchospasm despite pretreatment. Induced sputum is a potential source of information on the cellular and molecular mechanisms involved in airway inflammation. However, this procedure will likely remain a research tool for the evaluation of asthma in children because of technical considerations and standardization requirements.
September 2004 Page 463
The puzzle of IL-8 and the genetics of inflammation There is an important clinical feature that bronchial asthma, juvenile idiopathic arthritis (JIA), and respiratory syncytial virus (RSV)–triggered bronchiolitis have in common: the inflammatory reaction. Given that inflammatory processes are strongly influenced by genetic factors, some common genetic basis of all 3 diseases might be suspected. The article by Heinzmann et al in this issue of the Journal (p 671) focuses on the IL-8 pathway. IL-8 represents a strong inducer of inflammation. Several polymorphisms in its coding gene have been published, one
Finding NEMO Human mutations in the gene IKBKG on the X-chromosome that encodes the nuclear factor-jB essential modulator (NEMO) protein have been associated with the syndrome of ectodermal dysplasia and immunodeficiency in males. This syndrome is characterized by absent eccrine sweat glands, sparse hair, conical incisors, and combined immunodeficiency. Patients have severe bacterial infections and susceptibility to atypical mycobacteria. The NEMO protein serves as a critical link between important receptor systems and the transcription factor NFKB. When NFKB is appropriately activated by NEMO, it can travel into the nucleus to induce gene transcription. As
Safety and application of induced sputum analysis in childhood asthma The Childhood Asthma Management Program (CAMP) evaluated the long-term effects of budesonide and nedocromil compared with placebo in children with mild to moderate asthma. In this ancillary study by Covar et al, from the Denver CAMP site (p 575), biomarkers of airway inflammation were evaluated. At discontinuation of treatment, budesonide-treated patients had lower median sputum percent eosinophils, exhaled nitric oxide levels, and serum IgE and higher prebronchodilator FEV1% predicted than patients treated with placebo; no significant difference was noted between nedocromil- and placebo-treated patients. Higher sputum percent
J ALLERGY CLIN IMMUNOL
THE JOURNAL OF
Allergy Clinical Immunology AND
VOLUME 114
NUMBER 3
of them in close association with RSV-triggered bronchiolitis. The very same polymorphisms are now presented for the first time in association with bronchial asthma. This finding by itself might not be surprising; however, it is surprising to look at the kind of association. Bronchial asthma shows inverted association effects compared with bronchiolitis and, as well, in direct comparison with JIA. In other words, the genetic risk factor for bronchial asthma in the IL-8 gene represents a protective factor for bronchiolitis and JIA and vice versa. These findings might assist in our understanding of the pathophysiologic pathways in different inflammatory reactions. However, they underline as well the complexity of the genetic basis of inflammatory diseases.
a result of deficient NEMO activity, many functions of immune cells are impaired, including class switch recombination, specific antibody production, natural killer cell cytotoxicity, and Toll-like receptor responses. In this issue of the Journal, Orange et al (p 650), have identified a patient with an IKBKG mutation having the characteristic associated immunodeficiency but without ectodermal dysplasia. This patient is the first male reported to have immunodeficiency and normal ectoderm with an IKBKG mutation. The existence of this patient means that the absence of ectodermal dysplasia in an immunodeficient boy does not exclude IKBKG mutation as the etiology. It also suggests that important genotype/phenotype correlations are a feature of mutant NEMO molecules.
eosinophils was associated with atopy, higher bronchodilator reversibility, a lower FEV1/FVC ratio, higher exhaled nitric oxide levels, circulating eosinophil levels, sputum and serum eosinophil cationic protein levels, more prednisone courses during the treatment period, and greater asthma severity. Despite the relative safety and tolerability of sputum induction in children, 23% were not able to provide an adequate sputum sample for analysis. In 8%, sputum induction resulted in bronchospasm despite pretreatment. Induced sputum is a potential source of information on the cellular and molecular mechanisms involved in airway inflammation. However, this procedure will likely remain a research tool for the evaluation of asthma in children because of technical considerations and standardization requirements.
September 2004 Page 463